Thiazole formamidines



United States Patent This application is a continuation-in-part ofSerial No. 700,532, filed December 4, 1957 (now Uni-ted States Patent3,073,851, issued January 15, 1963); and a continuation of Serial No.153,693, filed November 20, 1961; Serial No. 153,694, filed November 20,1961 (now United States Patent 3,133,078, issued May 12, 1964); SerialNo.

153,695, filed November 20, 1961; Serial No. 153,715,

filed November 20, 1961; Serial No. 153,732, filed November 20, 1961;and Serial N 0. 153,733, filed November 20, 1961 (now United StatesPatent 3,135,755, issued June 2, 1964).

This invention relates to a process for the production of formamidinesfrom primary amines and to the novel compounds produced by the process.

The process of this invention comprises reacting a nonaliphatic primaryamine or a hydrohalide thereof with formamide or a lower alkyl formamidein the presence of an arylsulfonyl halide or a thionyl halide to producethe formamidine of the primary amine as illustrated by the followingreaction schemes:

(Ia) R1 11 R1 In the above formulae R represents a cyclic group, Xrepresents halogen and R and R each represents hydrogen or lower alkyl.

The cyclic groups represented by R in the formula above areunsubstituted or substituted monocyclic or polycyclic groups containingfive or more atoms and at least one double bond in the ring system. Oneor more electronegative groups may be attached to the ring. These cyclicgroups include aromatic hydrocarbons, hydroaromatic hydrocarbons,nitrogen, oxygenor sulfur-heterocyclics containing at least oneunsaturated linkage, and fused hydrocarbon or heterocyclic ring systemscontaining at least one unsaturated linkage in the ring system. Illustrative of the different types of cyclic groups, i.e., those represented byR in Formula I, are the following: phenyl, anthraquinone, biphenyl,pyridine, quinoline, pyrimidine, isoxazole, thiazole, triazine, uracil,benzothiazole, etc. The ring systems described above may hear one ormore substituents, e.g. carboalkoxy groups such as carbo-lower alkoxy,for example COOCH and di-lower alkylarninocarbo-lower alkoxy, forexample, COOC H,N(C H alkylamino; acylamino groups such as loweralkanoylamino, for example, NHCOCH ether .and thioether groups such aslower alkoxy and lower alkylmercapto, for example, CH O, C H O, anddi-lower alkylamino-lower alkoxy, for example, (C H NC H O; alkylgroups,

ice

Patented June 8, 1965 preferably lower alkyl such as methyl, ethyl,propyl, etc.; electronegative acid radicals derived from organic orinorganic acids, such as the halogens, SO N0 OH, COOH, 80 1-1, sulfamyl,acyl groups such as lower alkanoyl groups, for example, CH CO, aroylgroups such as benzoyl and substituted benzoyl groups, such astrifluoromethylbenzoyl, arsonyl, thiocyano, and the like.

The primary amino group which takes part in the condensation reactionmust be directly attached to the cyclic portion of the molecule. One ormore such primary amino groups present on the nucleus may react. Asindicated above, it is also necessary that there be at least oneunsaturated linkage in the ring system. The aryl sulfonyl halide whichmust be present includes benzenesulfonyl halides, :toluenesulfonylhalides, xylenesulfonyl halides, etc., preferably the first two,especially the chlorides thereof. Thionyl halides such as thionylchloride may also be used. Preferably monoalkyl formamide, such asmethyl-.

formarnide, and diloWer-alkyl formamide, such as dimethylforrnamide,diethylformamide, etc. are used in the process, lower alkyl formamides,in particular. Compounds bearing very strongly electronegativesubsti-tuents, e.g., p-nitroaniline, react also with formamide.

When the primary amine contains one or more electronegative substituentson the ring, either the free base itself or its hydrohalide willordinarily react according to the process of this invention. Stronglybasic primary amines, such as aminopyridine, aminoquinaldine, aniline,:p-phenetidine, etc., however, readily form sulfonamides withbenzenesulfonyl halides or toluenesulfonyl halides, especially in thepresence of an acidbinding agent such as pyridine and even formamide ordimethylformamide. 1

In order to produce formamidines from such strongly basic aminesaccording to the process of this invention, it is therefore usuallynecessary in this instance to use .as start.- ing material thehydrohalic salt, preferably the hydrochloride, of the amine. Then thereaction proceeds as in Formula I or Ia above and a formamidine insteadof a sulfonamide is obtained.

At least one equivalent of the formamide compound for each reactiveamino group is required. Preferably an excess of the formamide compoundis used so that it also acts as reaction medium. One equivalent of thesulfonyl halide for each reactive amino group must also be present.

In general the reaction proceeds at room temperature and is exothermic.The primary amine and arylsulfonyl halide or thionyl halide are merelyadmixed in excess formamide compound, the latter acting also as reactionmedium. It is convenient in some instances to apply heat in order toaccelerate and complete the reaction, but the temperature should notexceed C.

In many instances the hydrohalide or arylsulfonate salt of theformamidine will precipitate directly from the reaction mixture uponcooling. It is preferable, however,

to add to the reaction mixture an inert organic solvent such as alcohol,acetone, benzene, etc., in order to complete the crystallization of theproduct and to effect the removal of impurities and excess formamidecompound. In general, the strongeramines tend to produce hydrohalicsalts and the weaker amines tend to produce sulfonates. The acid saltsmaybe converted to the free base by neutralization with a basic reagentsuch as aqueous sodium carbonate, sodium hydroxide, etc. Any other acidsalt may be obtained from the free base by treatment with an equivalentproportionof the appropriate organic or inorganic acid. There may thusbe obtained such acid addition salts of the formamidines as thehydrohalides, benzenesulfonates, toluenesulfonates,

Listed below by structural formula are groups of novel compounds whichmay be produced according to this invention. The cyclic groups may bearone or more of the substituents described above.

More particularly the novel compounds to which this invention relatesare selected from the group consisting of compounds of the formuladenoted XV, wherein R and R each represents a member of the groupconsisting of hydrogen and lower alkyl, monovalent radical ringsubstituted derivatives thereof and salts of said compounds.

The monovalent radical ring substituents above referred to, besidesother formamidino groups, are preferably such groups as carboalkoxygroups such as carbolower alkoxy, for example COOC H and di-lower alkylaminocarbo-lower alkoxy, for example,

cooc rrssns n stituted benzoyl groups, such as trifluoromethylbenzoyl,arsonyl, thiocyano, and the like.

The novel compounds are useful in combatting bacterial, protozoal, viralor helmintic pathogens such as Streptococcus hemolyticus, Diplococcuspneumoniae, Encephalitis Col. SK, Mycobacterium tuberculosis, Trichomolzas vaginalis, Syphacia obvelata, etc. The compounds may beadministered orally or parenterally by incorporating therapeutic dosesin conventional vehicles.

The following examples are illustrative of the invention. Alltemperatures are in degrees centigrade.

Example 1 25 g. of p-diamino-diphenyl-sulfone were dissolved in 100 cc.of dimethylformamide. g. of p-toluenesulfonyl chloride were added andthe mixture was stirred. The mixture was stirred for about'one hour. Thetemperature rose to 74. The reaction mixture was then poured into 800cc. of water and cc. of 40% sodium hydroxide. The mixture was stirredfor 2 hours and then filtered. The crude crystalline product thusobtained was recrystallized by dissolving in 250 cc. of boiling benzene,filtering oil the insoluble impurities and adding 400 cc. of SkellysolveB (an n-hexane fraction) to the benzene filtrate. The mixture was keptovernight in the refrigerator. The crystallineN,N'-(p,p'-sulfonyldiphenylene)bis [N",N"-dimethylformamidine] thusobtained melted at 131 to 133.

The procedure described in the preceding paragraph was repeatedsubstituting 50 g. of benzenesulfonyl chloride for the 55 g. ofp-toluenesulfonyl chloride. The same product was obtained.

100 cc. of dimethylformamide, 25 g. of p-diamino-diphenyl-sulfone and 50g. of p-toluenesulfonyl chloride were reacted as described in the firstparagraph above. After the temperaturedropped to 40, 200 cc. of alcoholwere added and the mixture was heated to reflux. The clear solutionwhich resulted was filtered while hot. 100 cc. of alcohol were added tothe filtrate which was permitted to crystallize in the refrigerator.There was obtained white, crystalline N,N-(p,p-sulfonyldiphenylene)bis[N,N"-dimethylformamidine]p-toluenesulfonate.

Example 2 29 g. of mono-acetyldiamino-diphenyl-sulfone, 50 cc. ofdimethylformamide and 22 g. of benzenesulfonyl chlo- 'ride were stirredtogether, thetemperature rising to 64. The mixture was then stirred forone hour at 60. The reaction mixture was then drowned in 1000 cc. ofwater. While stirring, 125 cc. of a 20% sodium carbonate solution weredropped .in to neutralize the acid. After 24 hours the solid obtainedwas filtered, the filter cake was washed with ice water and sucked dryon a funnel. The solid was then dried at The p-acetamidophenyl-p-(dimethylaminomethyleneamino)phenyl sulfone was then crystallized fromacetic acid M.P..260 to 262.

Example 3 27 g. of procaine hydrochloride and 25 g. of p-toluenesulfonylchloride were stirred in 60 cc. of dimethylformamide. The temperaturerose to 45. The mixture was then stirred for 2 hours at 60. The mixturewas diluted with 300 cc. of acetone, stirred one hour at roomtemperature and then chilled to 5. The B-diethylaminoethyl p(dimethylaminomethyleneamino)benzoate dihydrochloride crystallized aswhite crystals, M.P. 205 to 206, from isopropanol-ethanol.

Example 4 30 g. of p-aminoacetanilide and 50 g. of p-toluenesulfonylchloride in 70 cc. of dimethylformamide were stirred and heated for onehour in a boiling water bath. The mixture was diluted with 50 cc. ofalcohol, refluxed for 1 hours, diluted with 300 cc. of acetone andfiltered at 10. The white, crystalline N-(p-acetamidophenyl)-N,N'-dimethylformamidine hydrochloride, M.P. 273 to 274, wasrecrystallized from methanol.

Example 5 28 g. of anthranilic acid and 50 g. of p-toluenesulfonylchloride in 80 cc. of dimethylformamide were reacted at 90 for one hour.100 cc. of alcohol were added, the mixture was refluxed for 30 minutesand then cooled to N-(o-carboxyphenyl)-N',N dimethyltormamidinehydrochloride crystallized. The white, crystalline hydrochloride wasrecrystallized from 80% alcohol, M.P. 169 to 171.

Example 6 N-(p-carboxyphenyl) N,N'-dimethylformamidine hydrochloride,obtained as white crystals melting at 236 to 237 upon crystallizationfrom 93% alcohol, was produced from 28 g. of p-aminobenzoic acidaccording to the procedure described in Example 5.

Example 7 15.5 g. of p-aminosalicylic acid and 25 g. or" p-toluenesulfonyl chloride in 50 cc. of dimethylformamide were stirred together.The temperature rose to 62. The mixture was diluted with 100 cc. ofalcohol and permitted to crystallize. TheN-(4-carboxy-3-hydroxyphenyl)-N',N- dimethylformamidinep-toluenesulfonate obtained was recrystallized from 90% ethanol, M.P.235.

Example 8 33 g. of o-aminophenol and 70 g. of p-toluenesulfonyl chloridewere reacted in 100 cc. of 'dimethylformamide. The temperature rose to70. The mixture was then heated one hour at 85. 25 cc. of'alcohol wereadded to the reaction mixture and it was refluxed for /2 hour. 300 cc.of acetone were added at 40 and the mixture was chilled to 10. TheN-(o-hydroxyphenyl)-N',N'-dimethylformamidine hydrochloride wasrecrystallized from alcohol and precipitated as white crystals, M.P.156.

Example 9 According to the procedure described in Example 8, there wasobtained from 33 g. of m-aminophenol, N-(mhydroxyphenyl) -N,N'dimethylformamidine hydrochloride as grayish crystals, M.P. 241 uponcrystallization from 95% alcohol.

Example 10 22 g. of p-aminophenyl and 50 g. of p-toluenesulfonylchloride were stirred in 100 cc. of dimethylformarnide. The temperaturerose to 55. The mixture was then heated for one hour at 90. 200 cc. ofether were added and, after stirring in an ice bath, the ether layer wasdecanted ofi. 300 cc. of acetone were added and the mixture waspermitted to crystallize in the refrigerator. TheN-(p-hydroxyphenyl)-N,N'-dimethylformamidine p-toluenesulfonate wasrecrystallized from alcohol, M.P. 209 to 210.

Example 11' 18 g. of 4-chloro-2-nitroaniline and 22 g. ofp-toluenesulfonyl chloride were stirred in 50 cc. of dimethylformamide,the temperature rising to 51. The mixture was then heated for one hourat 80 to 85. 300 cc. of acetone were added at 40 and the precipitatewhich formed was filtered off. The N,N-dimethyl-N'-(4-chloro 2nitrophenyl)formamidine hydrochloride was recrysallized from 95%alcohol, M.P. 205.

Example 12 16 g. of 4-nitro-2-aminotoluene and 25 g. ofp-toluenesulfonyl chloride were stirred in 50 cc. of dimethylforrnamide,the temperature rising to 63. The mixture was then stirred at roomtemperature for one hour. 300 cc. of acetone were added and the mixturewas placed in the refrigerator to crystallize. The N,N-dimethyl-N'-(2-methyl-S-nitrophenyl) formarnidine hydrochloride was recrystallized fromalcohol, M.P. 205.

Example 13 17 g. of 4-methoxy-Z-nitroaniline and 25 g. ofp-toluenesulfonyl chloride in 25 cc. of dimethylformamide were reactedas described in Example 12. The N,N-dimethyl-N- (Z-nitro 4methoxyphenyl)formamidine hydrochloride was crystallized fromacetonitrile, M.P. 198 to 200.

Example 14 26 g. of m-chloroaniline and 50 g. of p-toluenesulfonylchloride in 70 cc. of dirnethylformamide were stirred together, thetemperature rising to 74. cc. of alcohol were added, the mixture washeated /2 hour to reflux and then filtered.N-(3-chlorophenyl)-N,N-dimethylformamidine hydrochloride crystallizedfrom the filtrate. Upon recrystallization from acetonitrile-alcohol, thewhite crystalline hydrochloride melted at 233.

Example 15 32 g. of 2,5-dichloroaniline and 50 g. of p-toluenesulfonylchloride in 80 cc. of dimetnylformamide were stirred without heating forone hour then heated for one hour at 90. cc. of alcoholwere added, themixture was refluxed for /2 hour and then filtered. After addition of300 cc. of acetone to the filtrate,N-(2,5-dichlorophenyl)-N',N'-dimethylformamidine hydrochloridecrystallized. Upon recrystallization from alcohol, the hydrochloridemelted at 232.

Example 16 32 g. of 3,4-dichloroaniline and 45 g. of henzenesulfonylchloride in 100 cc. of dimethylformamide were stirred together, thetemperature rising to 60. The mixture was stirred for 2 hours at 60 andthen diluted with 300 cc. of acetone. The mixture was then filtered atroom temperature. The N-(3,4-dichlorophenyl)-N'-N' dimethylformamidinehydrochloride thus obtained, upon recrystallization from 90% alcohol,melted at 255 to 256. 3

Example 17 20 g. of 2,4,5-trichloroaniline and 25 g. ofp-toluenesulronyl chloride in 50 cc. of dimethylformamide were stirredat room temperature for one hour, then heated at 85 for one hour. Themixture was cooled to 40 and 200 cc. of acetone were added. CrystallineN,N-dimeth-" yll-(2,4,5 trichlorophenyhformamidine hydrochlorideprecipitated. The product was filtered, washed with acetone and dried at70. Upon recrystallization from acetonitrile-methanol, the productmelted at 225 to 227.

The hydrochloride obtained above was dissolved in water and madealkaline with 1 N sodium hydroxide. The free base,N,N-dimethyl-N-(2,4,5-trichlorophenyl) formamidine, was obtained aswhite crystals, M.P. 85 after recrystallization from acetonitrile.

Example 18 41 g. of 2,6-dichloro-4-nitroaniline and 42 g. of henlizedfrom alcohol, M.P. to 162.

Example 19 15 g. of aniline hydrochloride and 25 g. of benzenesulfonylchloride in 50 cc. of dimethylformamide were hydrochloride crystallizedfrom the filtrate.

. was obtained and the solution was filtered hot.

water and the solution was filtered while hot.

stirred at room temperature for one hour. The mixture was then heated ina water bath at 80 until a sample, treated with 1 N HCl and 1 N NaNOshowed no diazo reaction. The mixture was cooled to room temperature,200 cc. of acetone were added and the mixture was stirred in an icebath. The crystalline N-phenyl-N',N-dimethylformamidine hydrochloridewhich precipitated was filtered, dried at 75 and recrystallized fromisopropanol, M.P. 223 to 225.

The free base, N-phenyl-N',N'-dimethylformamidine, was obtained bytreating the hydrochloride with a dilute solution of sodium hydroxide,extracting with ether, concentrating the ether solution and distillingthe ether concentrate in vacuo. The base was obtained as a colorlessoil, B.P. 75 to 76/0.02 mm.

Example 20 35 g. of p-phenetidine hydrochloride and 50 g. ofptoluenesulfonyl chloride in 60 cc. of dimethylformamide were stirredtogether, the, temperature rising to 64. The diazo reaction of the masswas negative. The mixture was diluted with 400 cc. of acetone and placedin the refrigerator to crystallize. The mixture was filtered and the N(p ethoxyphenyl) N',N' dimethylformamidine p-toluenesulfonate wasrecrystallized from isopropanol, M.P. 169 to 170.

Example 21 28 g. of o-nitroaniline and 45 g. of p-toluenesulfonylchloride in 100 cc. of dimethylformamide were stirred together, thetemperature rising to 60. The mixture was then stirred and heated in awater bath for one hour at 90 to 95. The reaction mixture was thendiluted at 80 with 300 cc. of benzene and chilled to The N-(o-nitrophenyl)-N',N' dimethylformamidine. hydrochloride whichprecipitated was filtered off, Washed with benzene and recrystallizedfrom acetonitrile-ethanol, M.P. 224 to 225.

7 Example 22 28 g. of m-nitroaniline and 45 g. of p-toluenesulfonylchloride in 100 cc. of dimethylformarnide were stirred together, thetemperature rising to 62. The mixture was then heated for 2 hours at 90to 95, 200 cc. of alcohol were added and the mixture was refluxed for /2hour. The clear solution was filtered through a folded filter. N(m-nitrophenyl) N,N' -dimethylformamidine Upon recrystallization from90% alcohol, the compound melted Example 23 28 g. of p-nitroaniline and45 g. of p-toluenesulfonyl chloride, in 150 cc. of dimethylformamidewere stirred together, the temperature rising to 62. When thetemperature had fallen. to 40, the reaction mixture was heated at 85 forone hour. The mixture was diluted with 300 cc. of alcohol, refluxeduntil a clear solution The N- (p-nitrophenyl) N',N'. dimethylformamidinep-toluenesulfonate crystallized from the filtrate, M.P. 240 to 242.

42 g. of N-(p-nitrophenyl)-N',N-dimethylformamidine p-toluenesulfonatewere dissolved at 90 in 500 cc. of The filtrate was made alkaline withabout 30 cc. of sodium hydroxide. The .free base,N(p-nitrophenyl)-N',N'-dimethylformamidine, precipitated and wasrecrystallized from "benzene-Skellysolve B, M.P. 79 to 80.

Example 24 22 g. of arsanilic acid and 50 cc. of dimethylformarnide werestirred together. 25 g. of p-toluenesulfonyl chloride were added withthe temperature rising to 60. The reaction mixture was heated for onehour at 80, /2 hour at 95 and another half hour at 105. The mixture wascooled to 30, diluted with 250 cc. of acetone and then chilled to Themixture .was filtered after 2 hours 8. and the residue was washed withacetone. The 4-(N,N- dimethylformamidino)benzenearsonic acidhydrochloride was crystallized from dilute alcohol, M.P. 221 to 222.

Example 25 20 g. of I-amino-anthraquinone and 30 g. of p-toluenesulfonylchloride in 100 cc. of dirnethylformamide were heated at 95 for onehour. The mass was diluted with 250 cc. of alcohol, refluxed until aclear solution was ob tained and filtered while hot.1-(N,N-dimethylformami- (lino)anthraquinone toluenesulfonatecrystallized from the filtrate, M.P. 185.

Example 26 Example 27 18 g. of sulfanilic acid and 22 g. ofp-toluenesultonyl chloride in 60 cc. of dimethylformamide were stirredtogether, the temperature rising to The mixture was heated one hour at80. The diazo reaction was negative. The mixture was diluted at 80 with100 cc .of alcohol and stirred for one hour, then filtered at 10. TheN-(dimethylaminomethyleneamino)sulfanilic acid was crystallized fromalcohol, M.P. 308 (with dec.).

Example 28 17 g. of dianisidine hydrochloride and 20 g. ofbenzenesulfonyl chloride in 50 cc. of dimethylformamide were stirred atroom temperature for one hour, then heated at 85 for an additional hour.Thediazo reaction was then negative. The mixture was diluted at 60 with200 cc. of acetone, cooled to 10 and filtered. TheN,N'-bis[dimethylaminomethylene] 4,4'-o-dianisidine dihydrochloride Wascrystallized from alcohol, M.P. 268 (with dec.).

Example 29 24 g. of p-aminoazobenzene hydrochloride and 25 g. ofp-toluenesulfonyl chloride in 50 cc. of dimethylformamide were stirredtogether, the temperature rising to 56. The mixture was heated for /2hour at 80, diluted with 175 cc. of alcohol, heated to reflux for /2hour and the clear solution was then filtered while hot.p-(Dimethylaminomethyleneamino)azobenzene p toluenesulfonatecrystallized from the filtrate, M.P. 198 to 199.

Example 30 Hydrogen chloride gas was passed into a suspension of 47 g.of 2-aminopyridine in 300 cc. of toluene at a temperature of 5 to 15 C.until saturated. Z-Aminopyridine dihydrochloride separated as an oil.The oil was added to 200 cc. of dimethylformamide. 130 g. of p-toluenesulfonyl chloride were added with stirring. The mixture was stirred atroom temperature for one hour and then at 60 for 2 hours. It was thencooled to 20, diluted With 400 cc. of acetone and chilled to 10. Thewhite, crystalline 2-(N,N-dimethylformamidino)pyridine dihydrochloridewas then filtered off and recrystallized from methanol-acetone, M.P.178.

Example 31 37 g. of 2,6-diaminopyridine hydrochloride and g. of ptoluenesulfonyl chloride in 100 cc. of dimethylformamide were stirredtogether, the temperature rising to The mixture was stirred at 80 forone hour, 50 cc. of alcohol were added and the mixture was refluxed for/2 hour. 200 cc. of acetone were added at 20, the

mixture was stirred for one hour and then filtered at The filter cakewas dried in a desiccator over sulfuric acid. The2,6-bis-(N,N-dimethylformamidino)pyridine dihydrochloride wascrystallized from methanolacetone, M.P. 289 to 290.

Example 32 26 g. of 6-methoxy-8-aminoquinoline hydrochloride and g. ofbenzenesulfonyl chloride in 100 cc. of dimethylformamide were stirredtogether, the temperature rising to 61. The mixture was heated at 80 forone hour, diluted at 60 with 300 cc. of acetone, chilled to 10 andfiltered. The 6-methoxy-8-(dimethylaminomethyleneamino)quinclinedihydrochloride, upon crystallization from 90% alcohol, melted at 210 to212.

The free base, 6-methoxy-8-(dimethylaminomethyleneamino) -quinoline, wasobtained by dissolving the dihydrochloride obtained above in water andmaking the solution alkaline with 1 N sodium hydroxide. The free basecrystallized from acetonitrile in the form of white needles, M.P. 158.

Example 33 21.5 g. of 4,6-diaminoquinaldine dihydrochloride and g. ofp-toluenesulfonyl chloride in 150 cc. of dimethylformamide were stirredfor one hour at room temperature. The mixture was stirred at 90 for onehour. The diazo reaction was negative. The mixture was diluted at 60with 300 cc. of acetone, cooled to 20 and the precipitate was filteredoff. The 6-(dimethylaminomethyleneamino) 4-aminoquinaldinedihydrochloride was crystallized from dilute alcohol, M.P. 288.

The free base, 6-(dimethylaminornethyleneamino)-4- aminoquinaldine, wasobtained by dissolving the dihydrochloride obtained above in water andmaking the solution alkaline with sodium hydroxide. The free base wasobtained as off-white crystals upon crystallization from acetonitIile,M.P. 223 to 224.

Example 34 26 g. of Z-aminopyrimidine hydrochloride and 42 g. ofbenzenesulfonyl chloride in 50 cc. of dimethylformamide were stirredtogether, the temperature rising to 41. The mixture was heated at 90 forone hour and then diluted at with 300 cc. of acetone. N,N-dimethyl-N-(2pyrimidyDformamidine hydrochloride crystallized and was filtered at 10.The hydrochloride was recrystallized from acetonitrile, M.P. 212.

Example 35 23 g. of S-amino-3,4-dimethylisoxazole and g. ofp-toluenesulfonyl chloride in 50 cc. of dimethylformamide were stirredtogether, the temperature rising to 75. The mixture was heated for onehour at 85". It was then diluted at 30 with 400 cc. of acetone andfiltered at 10. The residue, N,N-dimetl1yl-N'-(3,4-dimethyl-5-isoxazohyl)formamidine p-toluenesulfonate was crystallized from alcohol, M.P.145.

Example 36 Example 37 21 g. of N,N-diallymelamine and 25 g. ofp-toluenesulfonyl chloride in 100 cc. of dimethylformamide were stirredfor one hour at room temperature. The mixture was heated for /2 hour atone hourat 80 and then /2 hour at 85. At room temperature it was dilutedwith 300 cc. of water and 30 cc. of 40% sodium hydroxide. The mixturewas stirred for 2% hours at room temperature and the white precipitatewas then filtered 0E. The Z-diallylamino-4-amino-6 (N,Ndimethylformamidine)-S-triazine was crystallized from acetonitrile',M.P. 174.

Example 38 2.5 g. of S-aminouracil and 5 g. of p-toluenesulfonylchloride and 6 cc. of dimethylformarnide were heated in a water bath atThe melt was diluted with 4 cc. of alcohol and 20 cc. of acetone. Theprecipitated 5-(dimethylaminomethyleneamino) 2,4dioxo-1,2,3,4-tetrahydropyrimidine hydrochloride was filtered at 10 andcrystallized from 85% ethanol, M.P. higher than 350.

Example 39 14 g. of p-nitroaniline and 22 g. of p-toluenesulfonylchloride in 50 cc. of formamide were stirred together, the temperaturerisingto 50. The mixture was then stirred at 60 for one hour and 70 for2 hours. cc. of alcohol were added and the mixture was heated to reflux.The clear solution was filtered while hot. N-(p-nitrophenyi) formamidinep-toluenesulfonate crystallized from the filtrate and was recrystallizedfrom alcohol, M.P. 202.

The procedure described above was repeated utilizing 20 g. ofbenzenesulfonyl chloride to obtain -(P nitrophenyl)formamidinebenzenesulfonate, M.P. 225 to 227.

Example 40 20 g. of p-nitroaniline, 35 g. of p-toluenesulfonyl chlorideand 50 cc. of diethylformamide were heated in a boiling water bath forone hour until a clear light yellow solution was formed. The solutionwas diluted with 100 cc. of alcohol, heated to reflux for 15 minutes andfiltered while hot. The filtrate was cooled to 10 and 200 cc. of icewater were added. N-(p-nitrophenyl) N',N'-diethylformamidinep-toluenesulfonate crystallized in needles. The compound was filtered,washed with a little ice water, dried in the oven and recrystallizedfrom dilute alcohol, M.P. to 162. 7

The free base, N-(p-nitrophenyl)-N',N-diethylfornramidine, was obtainedby dissolving the p-toluenesulfonate in water, filtering and making thefiltrate alkaline with aqueous sodium carbonate solution. The yellow,crystalline base melted at 59 to 60.

Example 41 pound melted at Example 42 41 g. of2-amino-6-hydroxybenzothiazole and 50 g. of p-toluenesulfonyl chloride,in 100 cc. of dimethylformamide were stirred together, the temperaturerising to 65. The mixture was heated and stirred for 2 hours at 80. Itwas diluted at 60 with 300 cc. of acetone. 2-(N,N-dimethylformamidino)-6-hydroxybenzothiazole hydrochlorideprecipitated, was filtered and dried, M.P.. 230.

15 g. of the hydrochloride obtained above were dissolved in 200 cc. ofwater at 60 and filtered. 50 cc. of sodium acetate solution (20%) wereadded to the filtrate. The free base,2-(N,N-dimethylformamidino)-6-hydroxybenzothiazole, precipitated, wasfiltered oil anddried, M.P. 237.

Example 43 22 g. of 2-(N,N-dimethylformamidino)-6-hydroxyben zothiazole,300 cc. ot.chlorobeuzene, 7 g; of sodium with sodium hydroxide.

M.P. 130 to 135.

methoxide and 50 cc. of methanol were stirred for one hour at roomtemperature. The methanol was then distilled off. g. ofdiethylaminoethyl chloride were added at 90 and the reaction mass washeated for 3 hours to reflux at 130. It was then cooled below 100, 200cc. of water and 10 cc. of sodium hydroxide were added and the mixturewas stirred for one hour. The chlorobenzene layer was separated, driedwith sodium sulfate, filtered and concentrated in vacuo. The oilyresidue was crystallized from acetonitrile and recrystallized frombenzine (B.P. to 60). The yellow crystalline 2-(N,N-dimethylformamidino)6 (,B-diethylaminoethoxy)benzothiazole melted at 69 to 70.

The free base obtained above was converted into the oxalate by mixing anether solution of the base with an ether'solution of oxalic acid. Theoxalate precipitated and was crystallized from methanol, M.P. 162 to163.

Example 44 34 g. of S-aminopyridine dihydrochloride and 45 g. ofp-toluene-sulfonyl chloride in 100 cc. of dimethylformamide were stirredtogether, the temperature rising to 71. The mixture was heated for onehour at 80. It was diluted at with 300 cc. of acetone and chilled to 10.The crystalline precipitate, 3-(N,N-dimethylformamidino)pyridinedihydrochloride, was filtered and recrystallizedfrom methanol-ethanol,M.P.228 (with 'dec.). Example 26 g. of 4-aminopyridine hydrochloride and44 g. of p-toluene-sulfonylchloride in 100 cc. of'dimethylformamide werestirred together, the temperature rising to 38. The mixture was heatedfor 2 hours at 60. A sandy precipitate formed. The mixture was dilutedwith 300 cc. of acetone, chilled to 10 and filtered. 4-(N,N-dimethylformamidino)pyridine dihydrochloride was obtained as whitecrystals, M.P. 260 to 261 (with dec.) upon crystallization frommethanol-acetonitrile.

Example 46 dried at 75 and crystallized from acetonitrile. The 2-dimethylaminomethyleneamino) -5-nitrothi azole hydrochloride melted at178 to 180.

Example 47 25 g. of p-diamino-diphenyl-sulfone and 50 cc. ofdimethylformamide were stirred. 26 g. of thionyl chloride were droppedin at a tempearture below 20. The

mixture was stirred for one hour at room temperature,

2 hours at to and 2 hours at to The diazo reaction was negative. Themixture was diluted at room temperature with 150 cc. of water. andfiltered The filtrate was made alkaline The white precipitate, N ,N'-(p,p' sulfonyldiphenylene)bis [N",N" dimethylformamidine], was filtered,washed with water, dried and crystallized from Skellysolve C (a normalheptane fraction),

through a folded filter.

Example 48 22 g. of p-aminophenol and 5 cc. of dimethylformamide werestirred. 26 g. of thionyl chloride were dropped in at a temperaturebelow 20. The mixture was stirred 12 droxyphenyl)-N,Ndimethylformamidinehydrochloride was recrystallized from methanol-acetone, M.P. "198 to200. By treatment of the hydrochloride with sodium carbonate solution,N-(p-hydroxyphenyl)-NN-dimethylformamidine precipitated. The free basewas crystallized from alcohol, M.P. 197 to 199.

Example 49 "69 g. of p-phenetidine hydrochloride and cc. ofdimethylformamide were stirred. 52 g. of thionyl chloride were droppedin at a temperature below 20. The temperature was permitted to riseslowly to 30. The mixture was then heated in a water bath to 40", onehour at 60, one hour at 80 and one hour at 90. The diazo reaction wasthen negative. The mixture was diluted with 200 ccyof water and thenmade alkaline at 15 to 22 with cc. of sodium hydroxide and 25 cc. ofsodium carbonate (20%). 300cc. of ether were added. The ether layer wasseparated, chilled in an ice bath and 20 g. of concentrated sulfuricacid were added. The ether was decanted 011. The residue wascrystallized from 200 cc. of acetonitrile and filtered. TheN-(pethoxyphenyl) N',N' dimethylformamidine sulfate melted at 158 to160.

Example 50 42 g. of p-nitroaniline and 100 cc. of dimethylformamide werestirred. 39 g. of thionyl chloride were added at a temperature below 20.The mixture was heated to 30 and the tempeart-ure then rose to 68.N-(p-nitrophenyl)-N',N-dimethylformamide hydrochloride crystallized. Themixture was diluted with 400 cc. of acetone and filtered. The residuewas sucked dry on a funnel and then dried in a desiccator over sulfuracid. The prodnot was recrystallized from alcohol, M.P. 261

Example 51 Example 52 15 g. of 4-aminoacetanilide was dissolved in 200cc. of boiling acetonitrile and the resulting solution filtered. 15 ccof isopropanol-hydrochloric acid (20%) was added to the filtratewhereupon 4-aminoacetanilide hydrochloride crystallized. A mixture of3.8 g. of 4-aminoacetanilide hydrochloride, 5 cc. of dimethylformamideand 5 cc. of benzene sulfochloride was heated to 95.

Following continued heating on a steam bath for 30 minutes, the reactionmixture was cooled to 30 and diluted with 50 cc. of acetone. Theresulting crystalline precipitate was filtered oif yielding4-dimethylaminomethyleneamin0)-acetanilide hydrochloride melting at 284-285. The free base was obtained by dissolving the hydrochloride salt inwater and rendering the resulting solution alkaline with sodiumcarbonate. The base crystallizes from water and melts at 186-188". Byheating 4-(dimethylaminomethyleneamino)-acetanilide with hydrochloricacid (1:1) to 95 for a short time, the resulting hydrolyzed compound,4-(dimethylaminomethylenean1ino)-aniline was obtained. It crystalizcd asthe dihydrochloride.

Example 53 g A mixture of 4 g. m-aminoacetanilide, 6 cc. ofdimethylformamide and 2.6 g. of methyl sulfochloride was heated to 110.Upon dilution with acetone, crystals of 3-(dimethylaminomethyleneamino)acetanilide hydrochloride precipitated and were filtered off, and uponrecrystallization from methanol melted at 278 Example 54 A mixture of 15g. of p-thiocyanoaniline, 30 cc. of dimethylformamide and 20 g. of:p-toluene sulfochloride was heated on a steam bath to 90 for 30minutes. The reaction mixture was then diluted with 200 cc. of acetoneand chilled to 10 whereupon l-(dimethylaminomethyleneamino) 4thiocyanobenzene hydrochloride crystallized. The product was filteredofi, washed with acetone and recrystallized from ethanol forming whitecrystals melting at 215-218 Reaction of 9 g. of p-thiccyanoanilinehydrochloride, 20 cc. of dimethylformamide and 10 g. of p-toluene sulfochloride yielded the same compound, also as white crystals of thehydrochloride melting at 215-218" (recrystallized from ethanol).

Example 55 A mixture of 2.5 g. of S-thiocyano-Z-aminobenzophenone, cc.of dimethylformamide and 2 g. of ptulene sulfochloride were heatedtogether at 85. A clear orange colored melt was obtained and was dilutedwith ca. 40 cc. of acetone, whereupon Z-(dimethylaminomethyleneamino) 5thiocyanobenzophenone hydrochloride crystallized as light yellowcrystals melting at 164. The product was water soluble.

Example 56 A mixture of 2.5 g. of 5-thiocyano-2-trifluoromethyl-Z-aminobenzophenone, 4 cc. of dimethylformamide, and 2 g. of p-toluenesulfochloride'was heated to 90 on a water bath. After 15 minutes themelt was diluted with water and rendered alkaline with sodium carbonatesolution. Upon standing, the first oily precipitate formed whitecrystals which were filtered off and washed with water. Uponrecrystallization from ethanol, S-thiocyano- 2'-trifiuoromethyl 2(dimethylaminomethyleneamino)- benzophenone was obtained as crystalsmelting at 123.5- 125.

Example 57 34 g. of sulfanilamide, 100 cc. of dimethylformamide and 42g. of benzene sulfochloride were stirred together whereupon the mixtureof the temperature rose to 80. It was then stirred for one hourwhereupon the temperature dropped to 60. Then 300 cc. of ethanol wereadded and the resulting mixture was permitted to stand for 24 hours,after which it was diluted with 400 cc. of water and the resultingprecipitate filtered ofi and crystallized from dioxane-water (1:1)yielding 4-(dimethylaminomethyleneamino)-benzene sulfonamide as whitecrystals melting at 221-223 Example 58 7.5 g. of1,4,5,8-tetraaminoanthraquinone, 40 cc. of dimethylformamide and 15 cc.of benzene sulfochloride were stirred together whereupon the temperatureof the mixture rose to 55. It was then heated for one hour at 90. Theresulting thick reaction mix was diluted with 100 cc. of acetone at 45and the resulting precipitate filtered off, yielding1,4,5,8-tetra-(dimethylaminomethyleneamino)-anthraquinone tetra-benzenesulfonate as olive green crystals. By reacting 1.5 g. of1,'4,5,1-tetraamino anthraquinone, 5 cc. of dimethylfo'rmamide and 2 cc.

14 of thionyl chloride,1,4,5,8-tetra-(dimethylaminomethyleneamino)-anthraquinonetetrahydrochloride was obtained as metallic shining crystals. Both thesulfonate and the tetra-hydrochloride were soluble in water.

Example 59 Example 60 25 g. of 2,6-diamino-3-phenylazopyridinehydrochloride and 100 cc. of dimethylformamide were stirred together and26 g. of thionyl chloride was added thereto below 20. to 60 and themixture was stirred for two hours at 60, following which it was dilutedwith 400 cc. of acetone at 40. The resulting solution was chilled to 10and then filtered. The filter cake so-obtained was dried at 60-70 andcrystallized from isopropanol yielding 2,6-bis-(N,N-dimethylformamidino) 3 phenylazopyridine dihydrochloride asyellow crystals.

Example 61 A mixture of 20 g. of 4-methylmercaptoaniline hydrochloride,40 cc. of dimethylformamide and 25 g. of p-toluenesulfonyl chloride wereheated on a steam bath to for one hour. The mixture was then cooled to40 and the reaction mass diluted with 350 cc. of acetone, whereuponwhite crystals of N-(p-methylmercaptophenyl) N',N' dimethylformamidinep-toluene sulfonate formed and were filtered oil with suction and thenairdried. Upon recrystallization from ethanol, the product melted at2ll212.

I claim:

1. A compound selected from the group consisting of compounds of theformula H-G-N R1 R -(i (")-N=CH-N and acid addition salts thereof,wherein R and R each represents a member selected from the groupconsisting of hydrogen and lower alkyl; and R represents a memberselected from the group consisting of hydrogen and nitro.

2. 2-dimethylaminomethyleneamino) 5 nitrothiazole hydrohalide.

3. 2 (dimethylaminomethyleneamino)-5-nitrothiazole hydrochloride.

4. N,N-dimethyl-N-(Z-thiazolyl)-formamidine hydrochloride.

No references cited.

IRVING MARCUS, Primary Examiner.

NICHOLAS S. RIZZO, Examiner.

The temperature of the mixture then rose UNITED STATES PATENT OFFICECERTIFICATE OF CORRECTION Patent No. 3,188,3l6 June 8, 1965 NorbertSteiger It is hereby certified that error appears in the above numberedpatent requiring correction and that the said Letters Patent should readas corrected below.

Column 9, line 71, for "N,N--diallyme1amine" read N,N- diallylmelaminecolumn 11, line 67, for "5 car" read 5O ccm column 12, line 31, for"dimethylformamide" read dimethylformamidine line 34, for "sulfur" readsulfuric line 172, after "4 g," insert of column 14, line 56, for "2dimethylaminomethyleneamino) read 2-(dimethylaminomethyleneamino) 1Signed and sealed this 21st day of December 1965c (SEAL) Attest: tRNESTW. SWIDER EDWARD J. BRENNER ttesting Officer Commissioner of Patents

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THEFORMULA